View in EDS PDF Full Text

Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.

Saved in:
Bibliographic Details
Title: Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.
Authors: Venkatraman, Aparna, He, Xi C., Thorvaldsen, Joanne L., Sugimura, Ryohichi, Perry, John M., Tao, Fang, Zhao, Meng, Christenson, Matthew K., Sanchez, Rebeca, Yu, Jaclyn Y., Peng, Lai, Haug, Jeffrey S., Paulson, Ariel, Li, Hua, Zhong, Xiao-bo, Clemens, Thomas L., Bartolomei, Marisa S., Li, Linheng
Source: Nature. 8/15/2013, Vol. 500 Issue 7462, p345-349. 5p. 4 Graphs.
Subjects: Stem cells, Epigenetics, Genetic regulation, DNA methylation, Cell proliferation, Deletion mutation
Abstract: The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells; however, a role for imprinting per se in adult stem cells remains elusive. Here we show upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term haematopoietic stem cells and their downregulation upon haematopoietic stem cell activation and proliferation. A differentially methylated region upstream of H19 (H19-DMR), serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression. We demonstrate that conditional deletion of the maternal but not the paternal H19-DMR reduces adult haematopoietic stem cell quiescence, a state required for long-term maintenance of haematopoietic stem cells, and compromises haematopoietic stem cell function. Maternal-specific H19-DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (an inactive form) from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation and eventual exhaustion of haematopoietic stem cells. Mechanistically, maternal-specific H19-DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partly rescues the H19-DMR deletion phenotype. Our work establishes a new role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells. [ABSTRACT FROM AUTHOR]
Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
FullText Links:
  – Type: pdflink
Text:
  Availability: 0
Header DbId: pbh
DbLabel: Psychology and Behavioral Sciences Collection
An: 89799247
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Venkatraman%2C+Aparna%22">Venkatraman, Aparna</searchLink><br /><searchLink fieldCode="AR" term="%22He%2C+Xi+C%2E%22">He, Xi C.</searchLink><br /><searchLink fieldCode="AR" term="%22Thorvaldsen%2C+Joanne+L%2E%22">Thorvaldsen, Joanne L.</searchLink><br /><searchLink fieldCode="AR" term="%22Sugimura%2C+Ryohichi%22">Sugimura, Ryohichi</searchLink><br /><searchLink fieldCode="AR" term="%22Perry%2C+John+M%2E%22">Perry, John M.</searchLink><br /><searchLink fieldCode="AR" term="%22Tao%2C+Fang%22">Tao, Fang</searchLink><br /><searchLink fieldCode="AR" term="%22Zhao%2C+Meng%22">Zhao, Meng</searchLink><br /><searchLink fieldCode="AR" term="%22Christenson%2C+Matthew+K%2E%22">Christenson, Matthew K.</searchLink><br /><searchLink fieldCode="AR" term="%22Sanchez%2C+Rebeca%22">Sanchez, Rebeca</searchLink><br /><searchLink fieldCode="AR" term="%22Yu%2C+Jaclyn+Y%2E%22">Yu, Jaclyn Y.</searchLink><br /><searchLink fieldCode="AR" term="%22Peng%2C+Lai%22">Peng, Lai</searchLink><br /><searchLink fieldCode="AR" term="%22Haug%2C+Jeffrey+S%2E%22">Haug, Jeffrey S.</searchLink><br /><searchLink fieldCode="AR" term="%22Paulson%2C+Ariel%22">Paulson, Ariel</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+Hua%22">Li, Hua</searchLink><br /><searchLink fieldCode="AR" term="%22Zhong%2C+Xiao-bo%22">Zhong, Xiao-bo</searchLink><br /><searchLink fieldCode="AR" term="%22Clemens%2C+Thomas+L%2E%22">Clemens, Thomas L.</searchLink><br /><searchLink fieldCode="AR" term="%22Bartolomei%2C+Marisa+S%2E%22">Bartolomei, Marisa S.</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+Linheng%22">Li, Linheng</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 8/15/2013, Vol. 500 Issue 7462, p345-349. 5p. 4 Graphs.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Stem+cells%22">Stem cells</searchLink><br /><searchLink fieldCode="DE" term="%22Epigenetics%22">Epigenetics</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+regulation%22">Genetic regulation</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+methylation%22">DNA methylation</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+proliferation%22">Cell proliferation</searchLink><br /><searchLink fieldCode="DE" term="%22Deletion+mutation%22">Deletion mutation</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells; however, a role for imprinting per se in adult stem cells remains elusive. Here we show upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term haematopoietic stem cells and their downregulation upon haematopoietic stem cell activation and proliferation. A differentially methylated region upstream of H19 (H19-DMR), serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression. We demonstrate that conditional deletion of the maternal but not the paternal H19-DMR reduces adult haematopoietic stem cell quiescence, a state required for long-term maintenance of haematopoietic stem cells, and compromises haematopoietic stem cell function. Maternal-specific H19-DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (an inactive form) from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation and eventual exhaustion of haematopoietic stem cells. Mechanistically, maternal-specific H19-DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partly rescues the H19-DMR deletion phenotype. Our work establishes a new role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=89799247
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1038/nature12303
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 5
        StartPage: 345
    Subjects:
      – SubjectFull: Stem cells
        Type: general
      – SubjectFull: Epigenetics
        Type: general
      – SubjectFull: Genetic regulation
        Type: general
      – SubjectFull: DNA methylation
        Type: general
      – SubjectFull: Cell proliferation
        Type: general
      – SubjectFull: Deletion mutation
        Type: general
    Titles:
      – TitleFull: Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Venkatraman, Aparna
      – PersonEntity:
          Name:
            NameFull: He, Xi C.
      – PersonEntity:
          Name:
            NameFull: Thorvaldsen, Joanne L.
      – PersonEntity:
          Name:
            NameFull: Sugimura, Ryohichi
      – PersonEntity:
          Name:
            NameFull: Perry, John M.
      – PersonEntity:
          Name:
            NameFull: Tao, Fang
      – PersonEntity:
          Name:
            NameFull: Zhao, Meng
      – PersonEntity:
          Name:
            NameFull: Christenson, Matthew K.
      – PersonEntity:
          Name:
            NameFull: Sanchez, Rebeca
      – PersonEntity:
          Name:
            NameFull: Yu, Jaclyn Y.
      – PersonEntity:
          Name:
            NameFull: Peng, Lai
      – PersonEntity:
          Name:
            NameFull: Haug, Jeffrey S.
      – PersonEntity:
          Name:
            NameFull: Paulson, Ariel
      – PersonEntity:
          Name:
            NameFull: Li, Hua
      – PersonEntity:
          Name:
            NameFull: Zhong, Xiao-bo
      – PersonEntity:
          Name:
            NameFull: Clemens, Thomas L.
      – PersonEntity:
          Name:
            NameFull: Bartolomei, Marisa S.
      – PersonEntity:
          Name:
            NameFull: Li, Linheng
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 15
              M: 08
              Text: 8/15/2013
              Type: published
              Y: 2013
          Identifiers:
            – Type: issn-print
              Value: 00280836
          Numbering:
            – Type: volume
              Value: 500
            – Type: issue
              Value: 7462
          Titles:
            – TitleFull: Nature
              Type: main
ResultId 1